ESTABLISHMENT OF MICE DEFICTENT IN A VASOACTIVE PEPTIDE BY GENE TARGETING AND THEIR APPLICATION TO PATHOPHYSIOLOGICAL ANALYSIS

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In the present study, we have clarified the novel developmental role and the implication in blood pressure regulation of ET-1 through the establishment of ET-1-knockout mice by gene targeting and their analysis. We hypothesized that ET-1 may serve as a mediator of the epithelial-mesenchymal interaction in the development of neural crest cells which plays an important role in the formation of the pharyngeal arches and cardiovascular system. Particularly, the phenotype of ET-1 knockout homozyotes (craniofacial abnormalities+great vessel malformations+ventricular septal defect) and human congenital diseases such as CATCH22 and velo-cardio-facial syndrome are very similar, suggesting that ET-1 knockout mice may give a clue to clarification of the genetic mechanism of these diseases and development of new therapeutic strategis. In ET-1 knockout heterozygotes, blood pressure was paradoxically elevated, indicating that ET-1 may not simply act as a pressor and the involvement of ET-1 in the regulation of cardiovascular homeostasis is rather complicated. Subsequently, we have found abnormalities in respiration and response to stress in addition to blood pressure elevation in ET-1 knockout mice. These findings have shed a light on the role of ET-1 in central cardiopulmonary regulation. In the elucidation of the pathophysiological role of ET-1, it would be of great use to make disease models inET-1 knockout mice. Establishment of disease models including atherosclerosis and hypertension in ET-1 knockout mice is in progress. Furthermore, we have succeeded in establishing the vessel-selective gene expression system using the ET-1 gene promoter region and ET-1-overexpressing mice using this system. Systematic analysis of both ET-1 knockout mice and ET-1-overexpression mice is expected to further elucidate the pahophysiological role of ET-1.